1-[alkyl], 1-[(heteroaryl)alkyl] and 1-[(aryl)alkyl]-7pyridinyl-imidazo[1,2-alpha]pyrimidin-5(1H)-one derivatives

ABSTRACT

The invention relates to an imidazo[1,2-a]pyrimidone derivative represented by formula (1) or a salt thereof, wherein: X represents a bond, an ethenylene group, and ethenylene group, a methylene group optionally substituted by one or two groups selected from a C 1-6  alkyl group, a hydroxy group and a C 1-4  alkoxy group; a carbonyl group, an oxygen atom, a sulfur atom, a sulfonyl group, a sulfoxide group or a nitrogen atom being optionally substituted by a C 1-6  alkyl group; R1 represents a 2,3 or 4-pyridyl group optionally substituted by a C 1-4  alkyl group, C 1-4  alkoxy group or a halogen atom; R2 represents a C 1-6  alkyl group, a C 1-2  perhalogenated alkyl group, a C 1-3  halogenated alkyl group, a benzyl group, a phenyl ring, a naphthyl ring, 5,6,7,8-tetrahydronaphthyl ring, a pyridyl ring, an indole ring, a pyrrole ring, a thiophene ring, a furan ring or an imidazole ring, the benzyl group and the rings being optionally substituted by 1 to 4 substituents selected from a C 1-6  alkyl group, a phenyl ring, a halogen atom, a C 1-2  perhalogenated alkyl group, a C 1-3  halogenated alkyl group, a hydroxyl group, a C 1-4  alkoxy group, a nitro, a cyano, an amino, a C 1-6  monoalkylamino group or a C 2-10  dialkylamino group; and n represents 0 to 3. The invention relates also to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β, such as Alzheimer disease.

This application is a National Stage entry under 35 U.S.C. § 371 ofInternational application No. PCT/EP01/10,725, filed Aug. 31, 2001,which is incorporated herein by reference in its entirety; which claimsthe benefit of priority to European Patent Application No. 00402411.3,filed Sep. 1, 2000.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral tauopathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitinilation dependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylabon and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseases.These include, in a non-limiting manner, Parkinson's disease,tauopathies (e.g. frontotemporoparietal dementia, corticobasaldegeneration, Pick's disease, progressive supranuclear palsy) and otherdementia including vascular dementia; acute stroke and others traumaticinjuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; peripheral neuropathies;retinopathies and glaucoma.

In addition GSK3β may find application in the treatment of otherdiseases such as: Non-insulin dependent diabetes (such as diabetes typeII) and obesity; manic depressive illness; schizophrenia; alopecia;cancers such as breast cancer, non-small cell lung carcinoma, thyroidcancer, T or B-cell leukemia and several virus-induced tumors.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease. Thus, the inventors of the presentinvention have identified compounds possessing inhibitory activityagainst GSK3β. As a result, they found that compounds represented by thefollowing formula (I) had the desired activity and were useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of the aforementioned diseases.

The present invention thus provides imidazo[1,2-a]pyrimidone derivativesrepresented by formula (I) or salts thereof, solvates thereof orhydrates thereof:

wherein:

-   X represents a bond, an ethenylene group, an ethynylene group, a    methylene group optionally substituted by one or two groups selected    from a C₁₋₆ alkyl group, a hydroxy group and a C₁₋₄ alkoxy group;-   a carbonyl group, an oxygen atom, a sulfur atom, a sulfonyl group, a    sulfoxide group or a nitrogen atom being optionally substituted by a    C₁₋₆ alkyl group;-   R1 represents a 2, 3 or 4-pyridyl group optionally substituted by a    C₁₋₄ alkyl group, C₁₋₄ alkoxy group or a halogen atom;-   R2 represents a C₁₋₆ alkyl group, a C₁₋₂ perhalogenated alkyl group,    a C₁₋₃ halogenated alkyl group, a benzyl group, a phenyl ring, a    naphthyl ring, 5,6,7,8-tetrahydronaphthyl ring, a pyridyl ring, an    indole ring, a pyrrole ring, a thiophene ring, a furan ring or an    imidazole ring, the benzyl group and the rings being optionally    substituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group,    a phenyl ring, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a    C₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₄ alkoxy group,    a nitro, a cyano, an amino, a C₁₋₆ monoalkylamino group or a C₂₋₁₀    dialkylamino group;-   and n represents 0 to 3.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as: Non-insulin dependentdiabetes (such as diabetes type II) and obesity; manic depressiveillness; schizophrenia; alopecia; cancers such as breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia andseveral virus-induced tumors.

As further preferred embodiments of the present invention, there areprovided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, tauopathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma, and the aforementioned medicament in the form ofpharmaceutical composition containing the above substance as an activeingredient together with one or more pharmaceutical additives.

The present invention further provides an inhibitor of GSK3β activitycomprising as an active ingredient a substance selected from the groupconsisting of the imidazo[1,2-a]pyrimidone derivatives of formula (I)and the salts thereof, and the solvates thereof and the hydratesthereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of the imidazo[1,2-a]pyrimidone derivatives of formula (I)and the physiologically acceptable salts thereof, and the solvatesthereof and the hydrates thereof; and a use of a substance selected fromthe group consisting of the imidazo[1,2-a]pyrimidone derivatives offormula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof for the manufacture of theaforementioned medicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedalkyl group having 1 to 6 carbon atoms, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexylgroup, and the like;

The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen have been substituted by a halogen atom, for example aCF₃ or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has not been substituted by a halogen atom;

The C₁₋₅ monoalkylamino group represents an amino group substituted byone C₁₋₅ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group and isopentylaminogroup;

The C₂₋₁₀ dialkylamino group represents an amino group substituted bytwo C₁₋₅ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group;

The ethenylene and ethynylene group represents respectively thefollowing groups:

The leaving group represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid. The acid-addition salts of the basiccompounds are prepared by standard procedures well know in the art whichinclude, but are not limited thereto, dissolving the free base in anaqueous alcohol solution containing the appropriate acid and isolatingthe salt by evaporating the solution, or by reacting the free base andan acid in an organic solvent, in which case the salt separatesdirectly, or is precipitated with a second organic solvent, or can beobtained by concentration of the solution. The acids which can be usedto prepare the acid-addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically-acceptablesalts, that is, salts whose anions are relatively innocuous to theanimal organism in pharmaceutical doses of the salts, so that thebeneficial properties inherent in the free base are not compromised byside effects ascribable to the anions. Although medicinally acceptablesalts of the basic compounds are preferred, all acid-addition salts arewithin the scope of the present invention.

In addition to the imidazo[1,2-a]pyrimidone derivatives represented bythe aforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention. Theimidazo[1,2-a]pyrimidone derivatives represented by the aforementionedformula (I) may have one or more asymmetric carbon atoms. As for thestereochemistry of such asymmetric carbon atoms, they may independentlybe in either (R) and (S) configuration, and the imidazo[1,2-a]pyrimidonederivative may exist as stereoisomers such as optical isomers, ordiastereoisomers. Any stereolsomers in pure form, any mixtures ofstereoisomers, racemates and the like fall within the scope of thepresent invention.

Examples of preferred compounds of the present invention are shown intable 1 hereinafter. However, the scope of the present invention is notlimited by these compounds.

Preferred compounds of the present invention represented by formula (I)include also:

-   (1) Compounds wherein R1 represents a 3- or 4-pyridyl group and more    preferably 4-pyridyl group, which may be substituted by a C₁₋₂ alkyl    group, a C₁₋₂ alkoxy group or a halogen atom; and/or-   (2) X represents a bond, an ethenylene group, a methylene group    optionally substituted, a carbonyl group, a sulfur atom, an oxygen    atom or a nitrogen atom optionally substituted.

More preferred compounds of the present invention represented by formula(I) include also:

-   (1) Compounds wherein R1 represents an unsubstituted 4-pyridyl    group;-   (2) Compounds wherein R2 represents a trifluoromethyl group, a    2,2,2-trifluoroethyl, a phenyl ring, a naphthyl ring, a    5,6,7,8-tetrahydronaphthyl ring or an indole ring, the rings being    optionally substituted; and/or-   (3) Compounds wherein X represents an ethenylene group, a methylene    group optionally substituted, a carbonyl group, a sulfur atom or an    oxygen atom.

Particularly preferred compounds of the present invention represented byformula (I) include:

-   1:    1-[2-(phenyl)ethyl]-7-pyridin4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   2: 1-[2-(1H-indol-3-yl)ethyl]-7-pyridin4-ylimidazo[1    ,2-a]pyrimidin-5(1H)-one,-   3:    1-[3-(phenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   4:    1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   5:    1-[3-(4-methoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   6:    1-[2-(phenoxy)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   7:    1-[3-(2-methoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   8:    1-[3-(2-chlorophenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   9:    1-[3-(2-methylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   10:    1-[2-(phenylthio)ethyl]-7-pyridin-4-ylimidazo[1,2a]pyrimidin-5(1H)-one,-   11:    1-[3-(2,5-dimethoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   12:    1-[3-(4-methylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   13:    1-[3-(4-trifluoromethylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   14:    1-[4-(phenyl)butyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   15:    1-[3-(phenyl)propyl]-7-pyridin-3-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   16:    1-(2-phenyl-2-oxo-ethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(    H)-one,-   17:    (S)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   18:    1-(4,4,4-trifluorobut-2-enyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   19:    (R)1-(4,4,4-trifluoro-3-hydroxybutyl)7-pyridinylimidazo[1,2-a]pyrimidin-5(1H)-one,-   20:    1-(4,4,4-trifluorobut-1-enyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   21:    1-[2-(2,5-dimethoxyphenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   22:    1-[3-(2-fluorophenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one-   23:    1-(3-phenyl-3-oxo-propyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   24:    1-[3-(pyridin-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   25:    (S)-1-(4,4,4-trifluoro-butyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   26:    1-[2-(2-methoxyphenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   27:    1-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   28:    1-[2-(4-phenyl-phenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   29:    1-[2-(3-methoxyphenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   30:    1-[2-(2-naphthyl)2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   31:    1-[2-(4-methylphenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   32:    1-[2-(4-fluorophenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   33:    1-[2-(4-chlorophenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   34:    1-(2-(4-fluorophenyl)-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,-   35:    1-(2-naphthyl-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,    and-   36:    1-(2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2a]pyrimidin-5(1H)-one.

As a further object, the present invention concerns also methods forpreparing the imidazo[1,2-a]pyrimidone compounds represented by theaforementioned formula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Imidazo[1,2-a]pyrimidone compounds represented by the aforementionedformula (I) may be prepared according to scheme 1.

(In the above scheme the definition of R1, R2, X and n are the same asthose already described for compound of formula (I)).

The 7-pyridin-4-ylimidazo[1,2a]pyrimidin-5(1H)-one derivativerepresented by the above formula (III), wherein R1 is as defined forcompound of formula (I), is allowed to react with a base such as sodiumhydride, sodium carbonate or potassium carbonate in a solvent such asN,N-dimethylformamide, N-methylpyrrolidine, N,N-dimethylacetamide orchloroform at a suitable temperature ranging from 0 to 130° C. underordinary air, then with a compound of formula (II), wherein R2, X and nare as defined for compound of formula (I) and L represents a leavinggroup preferably bromide or mesyl group, is added to obtain the compoundof the aforementioned formula (I).

Compound of formula (II) are commercially available or may besynthesized according to well-known methods of one skilled in the art.The compound of formula (III) may be prepared according to the methoddefined in scheme 2.

(In the above scheme the definition of R1 is the same as alreadydescribed.)

According to this method, the 3-ketoester of formula (V) is allowed toreact with a 2-aminoimidazole of formula (IV). The reaction may becarried out in the presence of an ammonium salt such as ammoniumacetate, in a alcoholic solvent such as methanol, ethanol and the likeor without, at a suitable temperature ranging from 25°–140° C. underordinary air.

Compounds of formula (V) or (IV) are commercially available or may besynthesized according to well-known methods of one skilled in the art.

For example compounds of formula (V), wherein R1 represent a pyridylgroup optionally substituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group ora halogen atom, can be prepared by reacting a nicotinic acid optionallysubstituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or an halogen, witha malonic acid monoester. The reaction can be carried out using methodswell known to one skilled in the art, such as for example in presence ofa coupling agent such as 1,1′-carbonylbis-1H-imidazole in a solvent suchas tetrahydrofuran at a temperature ranging from 20 to 70° C.

In the above reactions, protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, tauopathies(e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; cancers such as breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES

The present invention will be explained more specifically with referenceto the following general examples, however, the scope of the presentinvention is not limited to these examples.

Example 1 (Compound N^(o) 1 of Table 1)1-[2-(Phenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one(Z)-but-2-enedioate (1:1)

1.1. 7-Pyridin4-ylimidazo[1,2a]pyrimidin-5(1H)-one

A mixture containing 7.31 g (38 mmol) of ethyl3-(4-pyridyl)-3-oxopropionate, 5 g (38 mmol) of 2-aminoimidazolehemisulfate and 5.86 g (76 mmol) of ammonium acetate was heated at 140°C. during 18 h.

The cooled mixture was treated with 30 ml of acetonitrile and filteredand the precipitate was added to water and heated at reflux temperaturefor 30 min. The resulting solution was cooled and the precipitaterecovered by filtration. The crude product thus obtained wasrecrystallised from ethanol to give 3.0 g of pure product as a graysolid.

Mp: 368–370° C.

1.2. 1-[2-(Phenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H) one(Z)-but-2-enedioate (1:1)

A suspension of 0.1 g (0.47 mmol) of7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one in 4 ml of anhydrousN,N-dimethylformamide was treated with 72 mg (0.52 mmol) of potassiumcarbonate and the resulting mixture was heated at 70° C. for 30 min. 96mg (0.52 mmol) of 2-(phenyl)ethyl bromide was added and the reactionmixture was heated at 130° C. during 1 h.

The cooled solution was treated with water and extracted with ethylacetate. The organic phase was dried and evaporated to give crudeproduct which was purified by silica gel chromatography, eluting withdichloromethane/methanol in the proportions 100/0 to 95/5. The 0.338 gof pure product obtained in the form of free base was dissolved in hotethanol and treated with 1 equivalent of (Z)-but-2-enedioic acid. Thecooled solution was filtered to afford 0.12 g of solid.

Mp: 190–192° C.

Example 2 (Compound N^(o) 4 of Table 1)1-[3-(1H-Indol-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one.

2.1. 3-(1H-Indol-3-yl)propanol (J. Med. Chem. (1995), 38(11), 1998)

To a suspension of 4.8 g (126.8 mmol) of lithium aluminum hydride in 240ml of diethylether at 0° C. was added dropwise 10 g (52.8 mmol) of3-(1H-indol-3-yl)propanoic acid dissolved in 430 ml of diethylether andthe resulting mixture stirred at room temperature for 1 h.

The reaction mixture was diluted with 100 ml of diethylether at 0° C.and treated with excess of a saturated aqueous solution of sodiumsulfate. Further solid sodium sulfate was added and the organic phasewas filtered to remove salts. The solvent was evaporated to dryness togive 9 g (98%) of product as an oil.

2.2. 3-(1H-Indol-3-yl)propyl bromide (Chem. Pharm. Bull. (1988), 36(8),2853)

To a solution of 2 g (11.41 mmol) of 3-(1H-indol-3-yl)propanol in 40 mlof dioxane was added at room temperature 5.3 g (12.55 mmol) ofdibromotriphenylphosphorane and the resulting solution was stirredduring 18 h.

An excess of cyclohexane was added and the resulting precipitate wasfiltered and discarded. The solvent was evaporated to dryness to give2.7 g (99%) of product as an oil which was used in the subsequent stepwithout further purification.

2.3.1-[3-(1H-Indol-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one.

To a suspension of 0.10 g (0.47 mmol) of7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one in 3 ml of anhydrousN,N-dimethylformamide was added 0.072 g (0.52 mmol) of potassiumcarbonate and the resulting mixture was heated at 130° C. during 10 min.There is added 0.116 g (0.52 mmol) of 3-(1H-indol-3-yl)propyl bromideand heating is continued for 16 h.

The cooled suspension is treated with water, extracted with ethylacetate and the organic extracts dried over sodium sulfate. The crudeproduct was purified by chromatography on silica gel eluting with amixture dichloromethane/methanol/ammonia in the ratio 90/10/1 to afford0.11 g of pure product.

Mp: 201–203° C.

Example 3 (Compound N^(o) 10 of Table 1)1-[2-(Phenylthio)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-onehydrochloride (1:1)

To a suspension of 0.2 g (0.94 mmol) of7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one in 4.5 ml of anhydrousN,N-dimethylformamide was added 0.169 g (1.23 mmol) of potassiumcarbonate and the resulting mixture was heated at 70° C. during 20 min.There was added 0.267 g (1.23 mmol) of 2-bromoethylphenylsulphide andheating was continued at 130° C. during 1.5 h.

Water was added to the cooled mixture and the resulting solutionextracted with ethyl acetate. The combined extracts were washed withwater and evaporated. The crude product was purified by chromatographyon silica gel eluting with a mixture of dichloromethanelmethanol in theproportions 100/0 to 96/4 to obtain pure compound as free base. Thecompound was converted to the hydrochloride salt by addition ofhydrochloric acid to an ethanolic solution of the free base. There isobtained 0.133 g of product as a white solid.

Mp: 219–221° C.

Example 4 (Compound N^(o) 6 of Table 1)1-[2-(Phenoxy)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one(Z)-but-2-enedioate (1:1)

To a suspension of 0.4 g (1.88 mmol) of7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one in 6 ml of anhydrousN,N-dimethylformamide was added 0.312 g (2.25 mmol) of potassiumcarbonate and the resulting mixture was heated at 70° C. during 30 min.There was added 0.378 g (1.88 mmol) of 2-phenoxyethyl bromide andheating was continued at 130° C. during 2 h.

Water was added to the cooled mixture and the resulting solutionextracted with ethyl acetate. The combined extracts were washed withwater and evaporated. The crude product was purified by chromatographyon silica gel eluting with a mixture of dichloromethane/methanol in theproportions 100/0 to 96/4 to obtain pure compound as free base. Theproduct obtained in the form of free base was converted to the salt bytreatment with one equivalent of (Z)-but-2-enedioic acid. There isobtained thus 0.217 g of final product.

Mp: 158–160° C.

A list of chemical structures and physical data for compounds of theaforementioned formula (I) illustrating the present invention is givenin table 1. The compounds have been prepared according to the methods ofthe example.

In the table, R1 is an unsubstituted 4-pyridyl group (4-py) or 3-pyridylgroup (3-py), Ph represents a phenyl group, (S) indicates thestereochemistry of the carbon atom, and “_” in the structure of R2represents the bond attached to X.

TABLE 1

N° R1 X R2 n Mp ° C. salt 1 4-py CH₂ Ph 1 190–192 (1:1)(Z)-but-2-enedioate 2 4-py CH₂

1 195–198 (1:1) (Z)-but-2-enedioate 3 4-py CH₂ Ph 2 150–152 (1:1)(Z)-but-2- enedioate 4 4-py CH₂

2 201–203 base 5 4-py CH₂

2 170–172 (1:1) (Z)-but-2-enedioate 6 4-py O Ph 2 158–160 (1:1)(Z)-but-2-enedioato 7 4-py CH₂

2 192–194 (1:1) hydrochloride 8 4-py CH₂

2 197–199 (1:1) hydrochloride 9 4-py CH₂

2 189–191 (1:1) hydrochloride 10 4-py S

2 219–221 (1:1) hydrochloride 11 4-py CH₂

2 207–209 (1:1) hydrochloride 12 4-py CH₂

2 200–202 (1:1) hydrochloride 13 4-py CH₂

2 204–206 (1:1) hydrochloride 14 4-py CH₂ Ph 3 206–208 (1:1)hydrochloride 15 3-py CH₂ Ph 2 184–185 (1:1) hydrochloride 16 4-py CO Ph1 264–268 hydrochloride 17 4-py CH(OH) CF₃ 2 220–222 Base (S) 18 4-py ═CF₃ 1 187–188 base (trans) 19 4-py CH(OH) CF₃ 2 219–220 base (R) 20 4-py═ CF₃CH₂ 0 221–222 base (trans) 21 4-py CH₂

1 235–236 hydrochlorid 22 4-py CH₂

2 198–200 hydrochloride 23 4-py CO Ph 2 208–211 hydrochloride 24 4-pyCH₂

2 223–226 hydrochloride 25 4-py CH₂ CF₃ 2 262–264 hydrochloride 26 4-pyCH₂

1 175–177 base 27 4-py CO

1 231 hydrochloride 28 4-py CO

1 264–265 hydrochloride 29 4-py CO

1 231–232 hydrochloride 30 4-py CO

1 272–274 hydrochloride 31 4-py CO

1 266 Hydrochloride 32 4-py CO

1 232 hydrochloride 33 4-py CO

1 268–269 hydrochloride 34 4-py CH(OH)(rac)

1 219–220 base 35 4-py CH(OH)(rac)

1 217–218 hydrochloride 36 4-py CH(OH)(rac)

1 212–213 Hydrochloride

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Two different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCI, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta. Inhibitors were solubilised in DMSO (final solventconcentration in. the reaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated 33P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequence:

NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 is between 10 nanomolar to 1 micromolarconcentrations.

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1  30 mg Crystalline cellulose  60 mg Corn starch100 mg Lactose 200 mg Magnesium stearate  4 mg(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1  30 mg Olive oil 300 mg Lecithin  20 mg(1) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

1. An imidazo[1,2-a]pyrimidone compound represented by formula (I) or asalt thereof, or a hydrate thereof;

wherein: X represents a bond, an ethenylene group, an ethynylene group,a methylene group optionally substituted by one or two groups selectedfrom a C₁₋₆ alkyl group, a hydroxy group and a C₁₋₄ alkoxy group; acarbonyl group, an oxygen atom, a sulfur atom, a sulfonyl group, asulforide group or a nitrogen atom being optionally substituted by aC₁₋₆ alkyl group; R₁ represents a 2, 3 or 4-pyridyl group optionallysubstituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or a halogen atom;R₂ represents a C₁₋₆ alkyl group, a C₁₋₂ perhalogenated alkyl group, aC₁₋₃ halogenated alkyl group, a benzyl group, a phenyl ring, a naphthylring, 5,6,7,8-terahydronaphtyl ring, a pyridyl ring, an indole ring, apyrrole ring, a thiophene ring, a furan ring or an imidazole ring, thebenzyl group and the rings being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a phenyl ring, a halogenatom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group,a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, an amino, aC₁₋₆ monoalkylamino group or a C₂₋₁₀ dialkylamino group; and nrepresents 0 to
 3. 2. An imidazo[1,2-a]pyrimidone compound or a saltthereof, or a hydrate thereof according to claim 1, wherein R1represents an unsubstituted 4-pyridyl group or 3-pyridyl group.
 3. Animidazo[1,2-a]pyrimidone compound or a salt thereof, or a hydratethereof according to claim 1, wherein R2 represents a trifluorornethylgroup, a 2,2,2-trifluoroethyl, a phenyl ring, a naphthyl ring, a5,6,7,8-telrahydronaplithyl ring or an indole ring, the rings beingoptionally substituted.
 4. An imidazo[1,2-a]pyrimidone compound which isselected from the group consisting of: 1:1-[2-(phenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one, 2:1-[2-(1H-indol-3-yl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,3: 1-[3-(phenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,4:1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,5:1-[3-(4-methoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,6: 1-[2-(phenoxy)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,7:1-[3-(2-methoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,8:1-[3-(2-chlorophenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,9:1-[3-(2-methylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,10:1-[2-(phenylthio)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,11:1-[3-(2,5-dimethoxyphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,12:1-[3-(4-methylphenyl)propyl]7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,13:1-[3-(4-trifluoromethylphenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,14: 1-[4-(phenyl)butyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,15:1-[3-(phenyl)propyl]-7-pyridin-3-ylimidazo[1,2-a]pyrimidin-5(1H)-one,16:1-(2-phenyl)-2-oxo-ethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,17:(S)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin-4-yIimidazo[1,2-a]pyrimidin-5(1H)-one,18:1-(4,4,4-trifluorobut-2-enyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,19:(R)-1-(4,4,4-trifluoro-3-hydroxybutyl)-7-pyridin4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,20:1-(4,4,4-trifluorobut-1-enyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,21:1-[2-(2,5-dimethoxyphenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,22:1-[3-(2-fluorophenyl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,23:1-(3-phenyl-3-oxo-propyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,24:1-[3-(pyridin-3-yl)propyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,25:(S)-1-(4,4,4-trifluoro-butyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,26:1-[2-(2-methoxyphenyl)ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,27:1-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,28:1-[2-(4-phenyl-phenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,29:1-[2-(3-methoxyphenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,30:1-[2-(2-naphthyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,31:1-[2-(4-methylphenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,32:1-[2-(4-fluorophenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,33:1-[2-(4-chlorophenyl)-2-oxo-ethyl]-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,34:1-(2-(4-fluorophenyl)-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,35:1-(2-naphthyl-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,36:1-(2-(1,1,4,4,-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-hydroxyethyl)-7-pyridin-4-ylimidazo[1,2-a]pyrimidin-5(1H)-one,or a salt thereof, or a hydrate thereof.
 5. An imidazo[1,2-a]pyrimidonecompound or a salt thereof, or a hydrate thereof according to claim 2,wherein R2 represents a trifluoromethyl group, a 2,2,2-trifluoroethyl, aphenyl ring, a naphthyl ring, a 5,6,7,8-tetrahydronaphthyl ring or anindole ring, the rings being optionally substituted.
 6. A pharmaceuticalcomposition which comprises a compound according to claim 1 togetherwith one or more pharmaceutically acceptable additives.
 7. Apharmaceutical composition which comprises a compound according to claim2 together with one or more pharmaceutically acceptable additives.
 8. Apharmaceutical composition which comprises a compound according to claim3 together with one or more pharmaceutically acceptable additives.
 9. Apharmaceutical composition which comprises a compound according to claim4 together with one or more pharmaceutically acceptable additives.
 10. Apharmaceutical composition which comprises a compound according to claim5 together with one or more pharmaceutically acceptable additives.